Whereas the great majority of primary, penetrating keratoplasties succeed in human beings, an intolerably high proportion of allogeneic corneas grafted into so-called "high-risk" eyes fail. Immune rejection is regarded as the major cause of graft failure. Our long term goal is to understand the cellular and molecular immune processes that dictate (a) why primary orthotopic corneal allografts are so well tolerated (i.e. display immune privilege), and (b) why grafts placed in "high-risk" eyes fare so poorly. During the past 4 years we have made progress toward these goals by demonstrating that (a) the T cells primarily responsible for low-risk corneal graft rejection recognize donor alloantigens by the "indirect pathway" allorecognition, whereas (b) grafts in "high-risk" eyes are rejected by both "direct" and "indirect" alloreactive T cells. We have shown that rejection in "high-risk" eyes can be abrogated by pre-emptive induction of ACAID. In addition, we have demonstrated that the cornea graft contributes to the immunosuppressive microenvironment in which it is placed, and that that microenvironment is no longer "privileged" in high-risk eyes. Based on our findings, we have formulated three related hypotheses to guide our experiments for the next 5 years: Success or failure of orthotopic corneal allografts is dictated by (1) the capacity of the graft to display immune privilege; (2) the capacity of the anterior chamber and the graft bed to display immune privilege, and (3) the capacity of the recipient immune system to recognize graft-derived antigens and to mount an allodestructive or an alloprotective response. We describe three Specific Aims: 1. Define the cellular and molecular mechanisms that induce corneal allograft immunity, contrasting the induction and expression of allodestructive immunity with the induction of alloprotective immunity. 2. Determine the extent to which the cornea functions as an immune privileged tissue (a) when placed at a heterotopic, non-privileged site, and (b) when explanted in vitro. 3. Develop strategies to promote corneal allograft acceptance based on results accruing from Specific Aims 1 and 2. Our experiments will enable us to discern the relative importances that immune privilege of the cornea (as a tissue), and immune privilege of the anterior chamber (as a site) play in dictating success of orthotopic corneal allografts in both low- and high-risk eyes. Moreover, we anticipate that our results will suggest novel strategies that could be used therapeutically to promote graft acceptance in clinical situations where graft failure is all too common.